Trino Baptista

Body weight gain induced by antipsychotic drugs: mechanisms and management

Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management.

Long term administration of some antipsychotic drugs increases body weight and feeding in rats. Are D2 dopamine receptors involved

Long term administration of the antipsychotic drugs thioridazine, trifluoperazine, haloperidol, and sulpiride increased body weight in rats. This effect was found to be sex dependent, that is, while female rats were prone to gain weight, male rats did not. Chlorpromazine and fluphenazine decreased body weight in male rats but did not affect females. The mechanism of body weight gain was investigated with sulpiride. A linear relationship between dose of sulpiride and body weight gain was found. Also, sulpiride increased caloric intake, and both actions were counteracted by bromocriptine, a specific D2 receptor agonist. These results confirm that antipsychotic drugs affect feeding and body weight and suggest that hyperphagia and body weight gain might be mediated by blockade of dopamine receptors of the D2 type.

Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: A multicentric, double-blind, placebo-controlled trial

BACKGROUND Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables. METHODS Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment. RESULTS The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels. CONCLUSIONS Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.

Pharmacological management of atypical antipsychotic-induced weight gain.

Excessive bodyweight gain was reported during the 1950s as an adverse effect of typical antipsychotic drug treatment, but the magnitude of bodyweight gain was found to be higher with the atypical antipsychotic drugs that were introduced after 1990. Clozapine and olanzapine produce the greatest bodyweight gain, ziprasidone and aripiprazole have a neutral influence, and quetiapine and risperidone cause an intermediate effect. In the CATIE study, the percentage of patients with bodyweight gain of >7% compared with baseline differed significantly between the antipsychotic drugs, i.e. 30%, 16%, 14%, 12% and 7% for olanzapine, quetiapine, risperidone, perphenazine (a typical antipsychotic) and ziprasidone, respectively (p < 0.001).Appetite stimulation is probably a key cause of bodyweight gain, but genetic polymorphisms modify the bodyweight response during treatment with atypical antipsychotics.In addition to nutritional advice, programmed physical activity, cognitive-behavioural training and atypical antipsychotic switching, pharmacological adjunctive treatments have been assessed to counteract excessive bodyweight gain. In some clinical trials, nizatidine, amantadine, reboxetine, topiramate, sibutramine and metformin proved effective in preventing or reversing atypical antipsychotic-induced bodyweight gain; however, the results are inconclusive since few randomized, placebo-controlled clinical trials have been conducted. Indeed, most studies were short-term trials without adequate statistical power and, in the case of metformin, nizatidine and sibutramine, the results are contradictory. The tolerability profile of these agents is adequate.More studies are needed before formal recommendations on the use of these drugs can be made. Meanwhile, clinicians are advised to use any of these adjunctive treatments according to their individual pharmacological and tolerability profiles, and the patient’s personal and family history of bodyweight gain and metabolic dysfunction.

Are metabolic indices different between drug-naïve first-episode psychosis patients and healthy controls?

OBJECTIVE To compare glucose and lipid metabolism parameters between drug-naïve first-episode psychosis (FEP) patients with a diagnosis of schizophrenia spectrum disorder and healthy controls matched for age, ethnicity, and gender. METHOD Baseline evaluations of fasting glucose and lipid metabolism parameters and the oral glucose tolerance test were performed with FEP patients (n=38), having no more than 10 days of cumulative exposure to antipsychotic medication, and normal community controls (n=36). Analysis of variance (ANOVA) was conducted to examine between group differences. RESULTS FEP patients did not show a higher prevalence of the precursors to diabetes (impaired fasting glucose, impaired glucose tolerance, insulin resistance), and no significant difference in beta-cell function or lipid profile measures, compared to healthy controls. FEP patients showed a higher waist to hip ratio compared to controls. CONCLUSIONS FEP patients having a schizophrenia spectrum disorder do not differ from healthy controls, in their baseline measures of glucose and lipid metabolites, nor in the prevalence of diabetes or its precursors, before (or close to) the onset of antipsychotic treatment.

Extended release metformin for metabolic control assistance during prolonged clozapine administration: A 14 week, double-blind, parallel group, placebo-controlled study

BACKGROUND Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration. METHODS In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14. RESULTS MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET. CONCLUSIONS MET improves metabolic control during prolonged clozapine administration.

Testosterone modulates mesolimbic dopaminergic activity in male rats

Male rats were castrated before puberty. When they were adult, the activity of their mesolimbic dopamine system was tested by ventral striatum microdialysis. Amphetamine injections increased dopamine more in castrated rats than in normal rats. This exaggerated response was attenuated by testosterone replacement therapy. The mechanism by which androgens modulate the activity of the mesolimbic dopamine system is discussed.

Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives

BACKGROUND Clinical studies suggest that the second generation antipsychotics (APs) clozapine and olanzapine and to a lesser extent the typical antipsychotics may be associated with a procoagulant and proinflammatory state that promotes venous thromboembolism. We evaluated here several blood factors associated with coagulation and inflammation in AP-treated schizophrenia patients and their first-degree relatives. METHODS Procoagulant factors (fibrinogen and plasminogen activator inhibitor [PAI-1]), the anticoagulant factor antithrombin III [AT-III], and inflammation-related factors (C-reactive protein [CRP] and leptin) were assessed in patients chronically treated with clozapine (n=29), olanzapine (n=29), typical APs (n=30) and first degree relatives of clozapine (n=23) and olanzapine subjects (n=11). RESULTS The typical AP group had the highest CRP level (p=0.013) in spite of having the lowest body mass index (BMI). Patients as a single group had higher CRP levels than relatives (p=0.003). The typical AP group also had the highest AT-III levels (p=0.021). Fibrinogen levels did not differ between the groups (p=0.13). Olanzapine patients displayed the highest PAI-1 and leptin levels among the drug-treated subjects, but values were similar to those observed in their relatives, and were significantly correlated with the BMI. CONCLUSIONS A homogeneous negative profile of high inflammation and procoagulant factors along with low levels of anticoagulants was not detected in any group. While preliminary, our results suggest that the observed abnormalities were not related to a direct drug effect, but to elevated BMI (high PAI-1 and leptin in olanzapine-treated patients). We speculate that the high CRP in the typical AP group might be related to poor lifestyle habits, but this must we confirmed in future studies.

Lateral hypothalamic sites eliciting eating affect medullary taste neurons in rats.

A hypothetical functional relationship between the feeding area of the lateral hypothalamus and the medullary and pontine taste areas was assessed in rats. Multiple electrodes were implanted in the lateral hypothalamus and the animals which exhibited eating upon electrical stimulation were selected. Then under pentobarbital anesthesia, the hypothalamus was electrically stimulated while unit activity of medullary and pontine taste areas was recorded. Electrical stimulation of the hypothalamus at sites which elicited eating affected 22% of gustatory neurons, 13% of proprioceptive neurons sensitive to oropharyngeal stimuli but only 0.2% of the remaining nongustatory neurons. Electrical stimulation at nonfeeding sites affected 3% of the gustatory neurons. The electrical stimulation of the hypothalamus had the same inhibitory or excitatory effect on a given gustatory neuron as the sapid stimulation of the tongue did. These results are discussed in terms of the taste pathways and their possible role in electrically elicited feeding.

Antipsychotic Drugs and Reproductive Hormones: Relationship to Body Weight Regulation

Excessive body weight gain is an undesirable side effect of prolonged administration of antipsychotic drugs (AP), which affects health and interferes with treatment compliance. It has been suggested that hyperprolactinemia-induced endocrine and metabolic abnormalities, particularly in the gonadal steroids, might be involved in the development of this type of weight gain. To test this hypothesis, reproductive hormones, cortisol, dehydro-epiandrosterone-sulfate (DHEA-S), thyroid hormones, and body weight gain were assessed in 18 patients (9 men, 9 women) with mental disorders receiving AP who had been medication-free for at least 3 months before the study, and in 27 placebo-treated subjects (10 men, 17 women). In women, hormones were evaluated during several phases of the menstrual cycle. A significant weight gain was observed in men but not in women. Under AP administration, women displayed significantly lower serum levels of estradiol and progesterone, whereas in men the levels of free testosterone and DHEA-S were significantly lower than in controls. Hyperprolactinemia was observed in both sexes. The levels of follicle-stimulating hormone in women and luteinizing hormone in men were significantly elevated by treatment, thus suggesting that the functioning of the hypothalamus-pituitary gonads was preserved. In men, such an endocrine profile resembles that observed in subjects with primary obesity. Women under AP administration were found to be relatively hyperandrogenic because of decreased serum estradiol levels, whereas women with primary obesity are known to display actual increased levels of androgens. These endocrine abnormalities may contribute to the excessive weight gain observed after AP treatment, and these could be the target of novel pharmacological treatments.